EMPA-HEART Offers Mechanistic Clues for Empagliflozin’s Cardiac Benefits

CHICAGO, IL—Treating patients with type 2 diabetes and a history of stable coronary artery disease with empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, significantly reduces left ventricular mass, according to results from the EMPA-HEART study presented earlier this week at the American Heart Association 2018 Scientific Sessions.

The findings suggest the cardiovascular and heart failure benefits of the drug, which was initially approved for glycemic control in patients with type 2 diabetes, may be attributable to left ventricular remodeling, say investigators.

“There’s been profound results with empagliflozin, and other SGLT2 inhibitors, in terms of cardiovascular mortality and heart failure,” lead investigator Subodh Verma, MD (St. Michael’s Hospital, Toronto, Canada), told TCTMD. “Yet, the mechanism in which these agents act has been unclear. Specifically, whether these therapies have the ability to facilitate direct cardiac remodeling has been unknown.”

Elliott Antman, MD (Brigham and Women’s Hospital, Boston, MA), called EMPA-HEART an “important mechanistic study,” one that is particularly important to cardiologists. Type 2 diabetes, he said, is associated with progressive renal dysfunction, as well as increased risks of hypertension, heart failure, coronary artery disease, and atrial fibrillation. SGLT2 inhibitors have been shown to improve glycemic control and reduce body weight in addition to their beneficial effect on heart failure hospitalizations.

“The reduction in left ventricular mass is important since left ventricular mass is an independent predictor of cardiovascular events, including incident heart failure,” said Antman during the late-breaking clinical trial session.

Important Translational Clues

EMPA-HEART is a follow-up study to the EMPA-REG OUTCOME trial, which was published in 2015 in the New England Journal of Medicine. In that study of 7,020 patients with type 2 diabetes and high cardiovascular risk, empagliflozin use was associated with a lower risk of death from cardiovascular causes, hospitalization for heart failure, and death from any cause.

In EMPA-HEART, investigators randomized 97 patients with a history of type 2 diabetes and established coronary artery disease, such as prior coronary revascularization or a history of MI, to treatment with empagliflozin or placebo and assessed structure and function with cardiac MRI after 6 months of treatment. More than 90% of patients had high blood pressure, but rates of congestive heart failure were relatively low.

At 6 months, there was a significant reduction in left ventricular mass adjusted to body surface area among patients treated with empagliflozin (adjusted mean LVMi difference -3.35 g/m² vs placebo; P = 0.01). Additionally, there was a significant reduction in ambulatory blood pressure (adjusted difference –6.8 mm Hg; P = 0.03) and an increase in hematocrit levels when compared with the placebo-treated patients. There were no significant changes in N-terminal pro-brain natriuretic peptide or troponin levels.

“The interesting part here is that these results were seen in a population of patients that had relatively normal left ventricular mass to being with, and seen on top of ACE inhibitors and ARBs in patients with relatively preserved blood pressure and ejection fractions,” said Verma. “Despite that, we still see a reduction in left ventricular mass.”

In a prespecified subgroup analysis, however, the researchers observed markedly greater remodeling among patients with higher left ventricular mass index at baseline (> 60 g/m2).

Overall, Verma said the study provides “important translational clues” on the cardiac effects of empagliflozin, noting, like Antman, that left ventricular mass regression is closely linked with clinical outcomes. Although the studies have not been conducted, Verma believes the cardiac remodeling is likely a class benefit. “I would be inclined to say this is a class of medications that have a very similar effect on cardiovascular outcomes, and therefore could hypothesize that SGLT2 inhibitors, in general, have these benefits on reverse remodeling,” he said.

Turning his attention to the secondary endpoint changes—mean systolic blood pressure and hematocrit levels—Antman suggested that empagliflozin favorably affects cardiac preload and afterload, which would explain the reduction in left ventricular mass. Given the positive results from EMPA-REG OUTCOME and EMPA-HEART, as well as the new data from the DECLARE-TIMI 58 trial showing dapagliflozin (Farxiga; AstraZeneca) reduced the risk of heart failure hospitalizations, Antman said he plans to increase his use of SGLT2 inhibitors in patients with type 2 diabetes, especially if they have a history of heart failure or coronary artery disease.

Empagliflozin is approved for reducing the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. Canagliflozin (Invokana; Janssen), another SGLT2 inhibitor, is approved for reducing major adverse cardiovascular event risk in a similar patient population.